1. Field of the Invention
The present invention pertains to a stabilized pharmaceutical composition which comprises a mixture of (a) a pharmaceutical agent unstable at a pH above about 3.5; and (b) a stabilizing amount of an acidic pharmaceutically acceptable carrier to stabilize the pharmaceutical agent. The acidic pharmaceutically acceptable carrier is a dried premixture of a pharmaceutically acceptable carrier and an aqueous solution of an acid. The stabilized pharmaceutical composition has a pH value of less than about 3.5, and when stored at a temperature of about 50.degree. C. for about 4 weeks at about 27% relative humidity, retains at least about 80% of the pharmaceutical agent. This invention also pertains to both immediate release forms and sustained-release forms of the stabilized pharmaceutical compositions as well as to novel methods for preparing and using the stabilized pharmaceutical compositions and to stabilized pharmaceutical compositions made by the novel method.
2. Description of the Background
One of the requirements for an acceptable pharmaceutical composition is that it must be stable, so as not to exhibit substantial decomposition of the active ingredient during the time between manufacture of the composition and use by the patient. A number of drugs are known to undergo hydrolytic decomposition, which is one of the most common routes of drug decompositions. Further, hydrolytic decomposition can be influenced by light, oxidation, and pH. For example, diethylpropion hydrochloride is known to slowly hydrolytically decompose in aqueous solution at pH 3.5 and below, but rapidly decompose at pH 3.5 and above. Stephen M. Walters, "Influence of pH on Hydrolytic Decomposition of Diethylpropion Hydrochloride: Stability Studies on Drug Substance and Tablets Using High-Performance Liquid Chromatography", J. Pharm. Science 69, 1206 (1980). The hydrolytic decomposition of bupropion hydrochloride has also been shown to have similar pH dependence. S. Casey Laizure and C. Lindsay DeVane, "Stability of Bupropion and its Major Metabolite in Human Plasma", Therapeutic Drug Monitoring 7, 447 (1985).
U.S. Pat. No. 3,819,706 (Mehta) and U.S. Pat. No. 3,885,046 (Mehta) disclose the use of m-chloro-.alpha.-t-butylaminopropiophenone (bupropion) and m-fluoro-.alpha.-t-butylaminopropiophenone for the treatment of depression in mammals.
U.S. Pat. No. Re. 33,994 (Baker et al.) discloses a controlled release composition for the oral administration of bupropion hydrochloride. The composition releases about 10% to 45% of bupropion hydrochloride within two hours, about 25% to 70% of bupropion hydrochloride within four hours, and about 40% to 90% of bupropion hydrochloride within six hours.
U.S. Pat. No. 5,358,970 (Ruff et al.) discloses a solid pharmaceutical composition comprising bupropion hydrochloride and a pharmaceutically acceptable stabilizer. The stabilizer has an aqueous solution pH of about 0.9 to about 4 at an aqueous solution concentration of about 6% w/w. The composition, when stored for 4 weeks at about 50.degree. C. and at about 27% relative humidity, contains at least about 80% of the labeled amount of bupropion hydrochloride in the composition. The stabilizer is selected from the group consisting of L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid, and L-cystine dihydrochloride.
U.S. Pat. No. 5,427,798 (Ludwig et al.) discloses a controlled sustained-release tablet comprising 25 to 500 mg of bupropion hydrochloride and hydroxypropyl methylcellulose. The amount of hydroxypropyl methylcellulose to one part of bupropion hydrochloride is 0.19 to 1.1. The tablet has a surface to volume ratio of 3:1 to 25:1 cm.sup.-1 and a shelf life of at least one year at 59.degree. F. to 77.degree. F. The tablet releases between about 20 and 60% of bupropion hydrochloride in water in 1 hour, between about 50 and 90% in 4 hours, and not less than about 75% in 8 hours.
U.S. Pat. No. 4,743,450 (Harris et al.) discloses a pharmaceutical composition which contains a drug component which comprises a suitable amount of an ACE inhibitor which is susceptible to cyclization, hydrolysis, and discoloration; a suitable amount of an alkaline earth metal carbonate to inhibit cyclization and discoloration; and a suitable amount of a saccharide to inhibit hydrolysis.
U.S. Pat. No. 5,350,582 (Merslavic et al.) discloses a process for preparing stable formulation of enalapril sodium salt. The process includes suspending enalapril maleate in demineralized water and a stoichiometric amount of a corresponding sodium compound selected from the group consisting of sodium carbonate, sodium hydrogen carbonate and sodium hydroxide.
U.S. Pat. No. 5,292,520 (de Haan et al.) discloses an improved granulation process utilizing temperatures greater than 45.degree. C. and involving a mixture of a water-soluble acid addition salt of a poorly soluble basic drug and an excipient. The process consists of selecting a drug from the group consisting of chloropromazine, imipramine, promethazine, and mianserin, selecting an excipient from the group consisting of microcrystalline cellulose, lactose, and calcium hydrogen phosphate, and adding a pharmaceutically acceptable alkaline compound having a water solubility of at least 2 mg/ml to the mixture before or during heating. The pharmaceutically acceptable alkaline compound is present in an amount from about 0.5% to about 10% by weight.
U.S. Pat. No. 5,441,747 (de Haan et al.) discloses a dry pharmaceutical preparation consisting essentially of a water-soluble acid addition salt of a poorly soluble basic drug selected from the group consisting of apomorphine, chlorpromazine, imipramine, promethazine, and mianserin; an excipient selected from the group consisting of microcrystalline cellulose, lactose, and calcium hydrogen phosphate in an amount from about 30 to about 80% by weight and a water-soluble alkaline stabilizer in an amount from about 0.5 to about 10% by weight preparation. The stabilizer is selected from the group consisting of sodium bicarbonate, ammonium carbonate, sodium citrate, dibasic sodium phosphate, anhydrous dibasic sodium biphosphate, diammonium hydrogen phosphate, and sodium pyrophosphate.
U.S. Pat. No. 5,562,921 (Sherman) discloses a stable solid pharmaceutical composition comprising enalapril maleate and a carrier. The carrier is substantially free of microcrystalline cellulose, cellulose derivatives or cellulose polymers and calcium phosphate and free or substantially free of a disintegrant. At least 50% of the carrier consists of one or more pharmaceutically acceptable water-soluble substances not being cellulose derivatives or cellulose polymers. The carrier is substantially free of magnesium stearate and includes a lubricant which is not magnesium stearate.
U.S. Pat. No. 5,573,780 (Sherman) discloses a process of manufacture of a pharmaceutical solid composition comprising enalapril sodium. The process comprises i) a) mixing enalapril maleate with an alkaline sodium compound and at least one other excipient, adding water sufficient to moisten, and mixing to achieve a wet mass; or b) mixing enalapril maleate with at least one excipient other than an alkaline sodium compound, adding a solution of an alkaline sodium compound in water sufficient to moisten and mixing to achieve a wet mass thereby to achieve a reaction without converting the enalapril maleate to a clear solution of enalapril sodium and maleic acid sodium salt in water; ii) drying the wet mass; and iii) further processing the dried material into tablets.
European patent application no. 0 380 021 (Abbott) discloses an improved pharmaceutical preparation using tromethemine and dibasic potassium phosphate or calcium carbonate to enhance stability.
U.S. Pat. No. 4,591,592 (Chowhan) discloses a stable pharmaceutical composition comprising a therapeutically effective amount of an active ingredient which is a pharmaceutically acceptable acid addition salt of a thieno-pyridine derived compound and a non-toxic stabilizing amount of a pharmaceutically, non-volatile acidic compound which is ascorbic acid, benzoic acid, citric acid, fumaric acid, or tartaric acid, and at least one pharmaceutically acceptable excipient.
U.S. Pat. No. 5,225,204 (Chen et al.) discloses a stabilized pharmaceutical formulation of Levothyroxine sodium comprising a complex of Levothyroxine sodium and a water-soluble polyvinylpyrrolidone adsorbed on a cellulose compound in the form of a tablet.